The continuing increase in bacterial resistance to antibiotics is a significant worldwide problem. Although most research has focused on patterns of resistance in pathogenic organisms, the importance of commensal bacteria as reservoirs of antimicrobial resistance determinants is now beginning to be recognized. We seek a better understanding of antibiotic resistance genes, particularly those conferring beta-lactam resistance, in the oral streptococci. The discovery of altered penicillin-binding proteins (PBPs) as the basis of beta-lactam resistance in S. pneumoniae quickly led to the hypothesis that these pbp genes evolved by recombination with homologs from other streptococcal species, in particular the oral streptococci. This gave rise to mosaic sequences containing sequence blocks highly divergent from those of sensitive strains that encoded novel PBPs with decreased affinity for beta-lactam compounds. The contribution of such mosaic genes to the emergence of penicillin resistance is widely accepted. However, both the source and mechanism of dissemination of sequences giving rise to mosaic genes is not fully understood. We hypothesize that the genesis of mosaic low-affinity PBPs occurs in the oral streptococci through the accumulation and exchange of point mutations in pbp genes, and that the oral streptococci are a reservoir of antibiotic resistance genes that are exchanged between both commensal and pathogenic microorganisms. We will use the paradigm established for the PBPs of S. pneumoniae as a model for molecular studies of the pbp2x and pbp2b genes of the oral streptococci. Our analysis of pbp genes will be carried out in oral streptococcal isolates representing the species salivarius. This information will be extended to mixed growth studies that will document both the genesis and direct exchange of resistance genes between the oral streptococci, including S. pneumoniae, thus linking genetic exchange, the genesis of antibiotic resistance genes, and the role of the oral streptococci as a reservoir of antibiotic resistance determinants.